One of the essential elements for the growth, development and support of the vital functions of the body is iron. Iron is essential for hemoglobin synthesis and has a positive influence on the erythrocyte count and on the hematocrit value. Iron deficiency in the body causes states of anemia, a disorder that occurs frequently in patients of all ages.
Iron deficiency can also be treated orally, although this method often yields only a partial success due to the modest absorption of the trivalent iron or to the serious side effects (Blood, 1955, 10 35-45 “Acute intestinal Iron Intoxication I” and Blood, 1955, 10 46-51 “Acute intestinal Iron Intoxication II”); these effects occur following the administration of divalent or trivalent iron salts such as ferrous sulfate, ferrous ammonium sulfate, iron gluconate, ferrous succinate, ferrous fumarate, ferric-sorbitol-citrate complex, ferric sulfate, ferric succinate, ferric fumarate, ferric ammonium oxalate, et cetera.
Oral administration of iron salts, especially for extended periods or at high doses, is hardly feasible due to the risks linked to the gastric tolerability of divalent iron salts and to a risk of overdose due to the high absorption of said salts; for trivalent iron salts, instead, there is a tolerability and low absorption problem.
Accordingly, oral administration of iron is difficult to manage, even if theoretically it is easier and less expensive than parenteral administration, especially intravenous administration.
Therefore, the intravenous parenteral approach, despite having administration problems and being usually performed in a hospital or day hospital, is preferable due to certainty of absorption and, therefore, to documentable effectiveness.
Currently, for practical use, the physician has at his disposal a large number of preparations on the market, with considerable relative differences in their chemical, physical and pharmaceutical peculiarities. According to traditional classification, which is based solely on chemical peculiarities (A. Müller, Arzneim. Forsch., 24 (6), 880883 (1974)), all anti-anemic remedies are classified in four basic groups: iron salts, iron chelates with low molecular weight, sandwich complexes with low molecular weight and polynuclear complexes of ferric hydroxide with carbohydrates. In the treatment of anemias caused by iron deficit, the latter, i.e., parenteral preparations based on polynuclear complexes of ferric hydroxide, have proved themselves to be the most effective.
In order to administer these complexes, the most widespread parenteral approach is the intravenous one (iv). For this type of administration, preparations must have some particular chemical-physical and biological characteristics, such as good iron bioavailability correlated to the type of complex and to its chemical stability. Moreover, it is necessary to guarantee a lack of local or general side effects, such as anaphylactic shock or hepatic toxicity linked to the impurities derived from the breakdown of sugar, to the molecular weight of the complex and to the free iron contained in the compound.
Accordingly, the chemical-physical characteristics of the complex are closely tied to the type of sugar used, to the content of iron bonded in the complex, and to the molecular weight. All these characteristics also affect directly the stability and the bioavailability of the complex. Among the most widespread complexes of iron with carbohydrates authorized for intravenous administration there is, for example, iron dextran with high molecular weight (about 265 kD) marketed under the trademark Dexferrum®, iron dextran with low molecular weight (about 165 kD) marketed under the trademarks Cosmofer® and Pharmacosmos®, iron gluconate with a molecular weight lower than 50 kD and marketed under the trademark Ferlecit®, iron saccharate with a molecular weight comprised between 34-60 kD, marketed under the trademark Venofer® and iron carboxy-maltodextrin with a molecular weight higher than 100 kD, known as Ferinject® in Europe and as Injectafer□™ in the United States, where however it is still in the process of being approved by the FDA. The active ingredient of Ferinject®/Injectafer™□, i.e., a polynuclear complex between trivalent iron and activated maltodextrins (“VIT-45”) with a molecular weight comprised between 100,000 and 350,000 daltons, particularly 150,000 daltons, and its intravenous and intramuscular use are disclosed in WO 2007/081744. It should be noted that despite the fact that VIT-45 has been named “ferric carboxymaltose” by the USAN Council (a US national body that assigns ordinary names to new drugs, similar to the international nonproprietary names “INN” issued by the WHO), see http://www.ama-assn.org/ama1/pub/upload/mm/365/ferric_carboxymaltos.pdf, this definition actually is not suitable from a chemical point of view, because VIT-45 is obtained from pure maltodextrins with a DE of 5-20, or from mixtures of maltodextrins with a DE of 5-40, while maltose is a disaccharide, and therefore by definition has a DE of 50. The most appropriate name for VIT-45 would be, therefore, iron carboxy-maltodextrin.
Despite this very wide context, from the medical point of view an improvement is still needed because, according to Gasche et al. in Inflamm. Bowel Dis. 13 (12) 1545-1551 (12/2007), all these preparations in any case have specific peculiarities and limitations (see also Geisser et al. Arzneimittelforschung 42, Nr. 12 (1992) 1439-1452). From a clinical point of view, existing products may be divided into the following categories:
1) Fe-gluconate: intravenous and/or oral administration in some countries. This is a complex classified as type III based on the strength of the sugar-iron bond, which is defined as labile and weak, and therefore iron release occurs entirely over 4-6 hours.
2) Fe-saccharate: administered only intravenously with a pH of 10.5-11. This is a complex classified as type II because it is more stable than the previous one. The iron is released over the 8-12 hours that follow administration.
3) Fe-polymaltose: administered intravenously or intramuscularly. This is a complex classified as type I due to the particular stability of the iron-maltodextrin bond. The iron is released, therefore, over the 36 hours that follow administration and therefore it does not have immediate bioavailability.
4) Fe-dextran: administered intravenously. This is a complex classified as type I for the remarkable stability of the iron-dextran bond, which affects heavily the release of the iron, which occurs over the 72-96 hours that follow administration.
It is useful, in any case, to remember that among the ones described above, the preparations mainly used in treatment today are still the historically older ones, i.e., iron saccharate and iron-dextran, even though both have considerable risks for toxicity, which is due mainly to the adverse reactions, of the anaphylactoid type for dextran (Hamstra et al., “Intravenous Iron Dextran in Clinical Medicine” JAMA, 1980, 243, 17 1726-1732) and of acute toxicity for iron saccharate, due to the presence of labile iron and impurities (Zager et al., “Parenteral iron formulations: A comparative toxicologic analysis and mechanisms of cell injury.” Am. J. Kid. Dis., 2002, 40, 1, 90-103).
It should be noted that intramuscular application (by infusion or injection) of products that have physiologically acceptable pH values of the solutions is suitable only for hospital use, due to the high risk caused by side effects. For Ferinject® (VIT-45), the information leaflet (issued to licensee Syner-Med and indicating as owner of the AIM (marketing authorization) Vifor France SA) indicates only the intravenous path as usable, and states explicitly that the intramuscular administration path is not allowed, contradicting what was stated in WO 2007/081744.
Therefore, it is important to note that the products authorized for intramuscular administration are currently very few—and that with these products important side effects often occur due to the inherent characteristics of the complex or due to the type of intramuscular administration, for example infusion or bolus injection.
Moreover, to the extent of the Applicant's knowledge, even today there are no products on the market that are authorized for subcutaneous administration.
This leads to the need to have available, in the treatment of anemic states due to iron deficiency, new active ingredients/products that allow simple administration, intramuscularly and/or optionally also subcutaneously, and also allow home use and not only hospital use.